Geron Corporation, Menlo Park, CA Outline GRNVAC1 and GRNVAC2

Nucleic Acid Based Vaccines: Case Study: GRNVAC1 hTERT-LAMP mRNA Transfected Autologous DC

The iSBTC Oncology Biologics Development Primer Gaithersburg, MD, February 29, 2008 Laurence Elias, M.D. Executive Director, Oncology Clinical Development Geron Corporation, Menlo Park, CA Outline GRNVAC1 and GRNVAC2

• Rationale for telomerase as target for immunotherapy • Rationale for hTERT-LAMP mRNA transfected DCs as immunotherapy • Discussion of AML Phase II study: – Manufacturing and regulatory implementation – Design, objectives and clinical execution • Practical lessons of implementing an mRNA transfected autologous cell POC study – Preview: Manufactured product→Patient! • What comes next? – GRNVAC2: an allogeneic, bulk manufactured hESC-DC follow- on product for broader development Structure and Function: Telomeres and Telomerase

TELOMERES • TTAGGG repeats at ends of all chromosomes • Shorten with cell division • Accelerated loss under stress

TELOMERASE •hTERT = catalytic protein subunit •hTR: Template RNA • Synthesizes telomeric DNA • May have other roles (eg, “capping,” stress resistance) Hallmarks of Cancer (Hannahan and Weinberg, Cell, 2002)

Cellular immortalization by telomerase is a requisite step for carcinogenesis hTERT as a TAA: Tumor vs. Normal Cytotoxicity

hTERT/ Cancer Cells hTERT/ Normal Cells

• Overexpressed • Low expression most normal cells • Transient expression activated or stem/progenitor cells • Sensitive to CTLs with • Low or no sensitivity to hTERT specificity for TERT CTLs: + – Vonderheide et al, 1999, – DCs, keratinocytes, CD34 ; 2001, etc. Vonderheide et al, 1999 – Su et al, 2002 – CFUs/LTC, in vitro; Danet- Desnoyers et al, 2005 – Minev et al, 2000 – CFUs, LTC-ICs pre-/post – Nair et al, 2000, 2005 vaccination; Brunsvig et al,06 • Clinical studies without normal stem cell effects hTERT-LAMP mRNA DCs: Discovery & Early Development

• mRNA Pulsing of DCs yields superior antigen presentation and anti-tumor immunity; Nair, Gilboa et al, J. Exp. Med., Int. J Cancer, Nature Biotechnology, 1996 to 1999 • TERT mRNA transfected DCs in murine models: induced CTLs and produced anti-tumor immunity in mice; Nair et al, Nature, 2000 • Transfection with hTERT-LAMP Chimeric RNA enhances CD4+ response; Nair et al, Cancer Res, 2002 • Prostate Ca Phase I Trials at Duke: – hTERT vs hTERT-LAMP – 3 vs. 6 injections: Su et al, JI, 2005 – Prime boost regimens: Unpublished Study Reports Duke Prostate Ca Phase 1 Trial J. Immunol. 174: 3798 (2005)

• 23 Subjects Vaccinated • Generally Well Tolerated • Marked Anti-Telomerase Immune Response After Six Weekly Vaccinations • hTERT-LAMP Induces CD-4+ As Well As CD-8+ Anti-Telomerase T Cells • Impact On Circulating Tumor Cells And PSA Doubling Times

Telomerase Specific Immune Response Clearance of Circulating Tumor Cells (9/10 Patients)

VACCINATION AJG-18AJG-18 06-LMP 1 2 3 1200 Immunization 1000 900 1212345 345 6 100 600 10 300 CD8 1 CD4

0 mRNA PSA Pre1234561 78901 11162 0 - 4 0 2 4 6 26 Study Period (weeks) Prolongation of PSA Doubling Time

FSH-19FSH-19 Six Weekly Doses (n=5)

1200 Immunization X 12 345 6 900 100 100.0 600 50

300 30 CD8 20 0 CD4 X Pre 1 2 3 4 561 7 8 901 112 16 10 Study Week 5 3 X 2 X 1 2.9 PRE POST GRNVAC1 Boost Optimization (Subsequent Studies)

Subjects Boosted 6 Times Biweekly Up to 45 Weeks After Prime

6 Injections 6 Injections

1000 T Cells

+ 800

CD8 600 5 400

Spots/10 200 0 -10 -5 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105 Study Weeks

5 -10 -5 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105 4 3 2 1

Serum PSA ng/ml 0 -10 -5 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105 Study Weeks GRNVAC Program: Geron Development

• Geron, in collaboration with T. Cech, clones hTERT: 1997 • Geron licenses Duke method of ex vivo DC production and RNA transfection from Argos Therapeutics, Inc: 2004 • Tech transfer: Duke to Geron Product Development: 2004-2005 • Tech transfer: Geron to Lonza cGMP manufacturing: 2005-2006 • RAC and IND filings/approvals for Geron studies: 2006 • Site qualification, training, approvals, contracting: 2007 • First patients accrued: AML remission Phase II POC: 2007 • Future transition to second generation product: hES-DC (GRNVAC2) GRNVAC1 hTERT mRNA Transfected DC Production

Incubation with cytokines

Leukapheresis harvest Ficoll centrifugation Monocyte Immature DCs enriched PBMCs

hTERT-LAMP mRNA Transfection mRNA (Electroporation) Plasmid

DC maturation: Mature DCs for Further incubation; Cryopreserved harvest DC Vaccine additional cytokines (Phenotyping, testing; disposition 1 x 107 viable cells/ dose post-thaw) GRNVAC1 Manufacturing Product Flow

Clinical Trial Site CMO Geron (Lonza)

Leukapheresis

Leukapheresis GRNVAC1 Path of Product Manufacturing Product GRNVAC1 Product

Paperwork QA Review of Cryo-Storage Batch Production Records

GRNVAC1 Cryo-Storage Disposition Product

Patient Rationale for AML Trial

– High telomerase expression in high risk varieties with unmet medical need – Remission as MRD setting with potential for monitoring – Timing: CR → Consolidation → Off Chemo/Observe – Intersperse leukapheresis with consolidation, vaccinate after consolidation completed – Immune response important for AML (eg, graft vs leukemia effect) Phase II Trial in AML Patients in CR

• To test ability to generate anti-hTERT immune response among intermediate-to-high risk AML patients • Eligibility: – Intermediate/high risk cytogenetics or other high risk molecular – Within 6 months of CR1 or in CR2 – Completed at least one cycle of consolidation – May complete 1 to 3 additional cycles of consolidation after leukapheresis and before start of vaccination – In CR or early relapse at time of start of vaccination • Primary Objective: – Feasibility and Safety • Secondary objectives: – hTERT ELISPOT response in majority of patients – PFS – Candidate biomarker for MRD response: WT1 PCR – Observe responses to “early relapse” (detected in between leukapheresis and vaccination) Phase II AML in AML Patients in CR

• Enroll up to 30 patients; assure > 20 evaluable (> 2 vaccinations) • Vaccination Schedule: – 6 weekly intra-dermal injections – 1 month rest – 6 boost injections every other week – Monthly extended post-boost vaccination (dependent upon product yield and continued CR) • Investigators/Sites: – Dr. John DiPersio, Washington University – Dr. William Blum, Ohio State – Dr. Robert Collins, UTSW – Dr. Hanna Khoury, Emory University • Status: – Successful harvest, manufacturing, vaccination of initial patients GRNVAC1 Case Study “Talking Points”

Challenges, Issues, Lessons Learned: Strategic, Regulatory, Operational Practical Implications of Manufacturing & Regulatory Aspects of mRNA Transfected Autologous Product

• RAC Review; RNA→ • IBC Approval at sites

• cGMP manufacturing → • Capacity limited; scheduling; identifiers • Yields vary

• Cryopreserved product, • Dose preparation steps at sites required: excipients → training and maintaining trained status

• Time patients stable and remain on study • Process time; lot release testing from enrollment to vaccination including 28 day mycoplasma → • Input material a source of variability • Clinical populations differ (host • Immunomonitoring, including test factors and response) → qualification, sample collection and prep

• POC Phase II design for • Design, population, endpoints may differ GRNVAC1 (patient specific) → for future product (GRNVAC2) **Autologous product → complex site implementation** • Key Lesson: Challenge goes beyond direct production steps: Think through all the steps from the site’s point of view! • Multiple facilities and staff at each site must be “on board:” – Leukapheresis – PBMC preparation for immunologic testing – Cryo-storage – Thawing, washing cells for delivery – CFR compliant sterility testing • “On board” includes: – Identification, qualification, documentation – Training in standardized protocol specific procedures – Staff changes during course of study; periodic renewal – Scheduling and coordination of multiple components at site and with sponsored centralized manufacturing facility • No “magic bullet;” just great sites, good preparation, communication and team-work! Acknowledgements

Lonza (Walkersville) Manufacturing, Quality Quality and Project Management • Naymisha Patel Teams • Madelyn Marino Investigators (and their coordinators): • Pauline Yuen • John DiPersio, Washington University • William Blum, Ohio State Immunological Monitoring • Robert Collins, UTSW • Anita Reddy • Hanna Khoury, Emory University • Glenn Dawes • Rohini Vekhande Geron Clinical • Catherine Howard Manufacturing • David Rhodes • Sean Cullen • Neeru Batra • Erwin Estigarribia Process Sciences • Jerrod Denham • Ralph Brandenberger • Yan Li Management • Rashi Srivastava • Melissa Kelly-Behrs • Lavanya Telukuntla • Wen Bo Wang • Anthony Davies • Jiwei Yang • Jane Lebkowski • Fabio Benedetti